The Protection of Midazolam Against Immune Mediated Liver Injury Induced by Lipopolysaccharide and Galactosamine in Mice

Objectives: Liver macrophages agitated by Lipopolysaccharide (LPS) can enhance immuno-inflammatory responses in the liver which mediate liver injury and result in dysfunction. Midazolam has been reported to have inhibitory effects on activated immunity and escalated inflammation, however, what the effects of midazolam on the liver injury caused by excessive immuno-inflammatory response in sepsis, and what influence it will exert on inflamed liver macrophages need to be elucidated.Methods: In the present study, LPS and galactosamine-induced acute liver injury mice were used to observe the effect of midazolam in vivo. LPS-stimulated bone marrow cells were used to evaluate the influence of midazolam on monocytes in vitro.Results: Midazolam prevented liver tissue injury and decreased serum alanine transaminase (ALT) level in LPS plus galactosamine treated mice. Mechanistically, midazolam suppressed tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) produced by LPS stimulated liver macrophages in vivo and bone marrow monocytes in vitro, and reduced the expression of major histocompatibility complex class II (MHC II), cluster of differentiation 40 and 86 (CD40 and CD86) on the cell surface. These results could be reversed by PK-11195, a peripheral benzodiazepine receptor (PBR) blocker.Conclusion: Midazolam can prevent liver from LPS-induced immune mediated liver injury by inhibiting inflammation and immune activation in liver macrophages

Ultrasmall Glutathione-Protected Gold Nanoclusters as Next Generation Radiotherapy Sensitizers with High Tumor Uptake and High Renal Clearance

Radiotherapy is often the most straightforward first line cancer treatment for solid tumors. While it is highly effective against tumors, there is also collateral damage to healthy proximal tissues especially with high doses. The use of radiosensitizers is an effective way to boost the killing efficacy of radiotherapy against the tumor while drastically limiting the received dose and reducing the possible damage to normal tissues. Here, we report the design and application of a good radiosensitizer by using ultrasmall gold nanoclusters with a naturally occurring peptide (e.g., glutathione or GSH) as the protecting shell. The GSH coated gold nanoclusters can escape the RES absorption, leading to a good tumor uptake (8.1% ID/g at 24 h post injection). As a result, the as-designed Au nanoclusters led to a strong enhancement for radiotherapy, as well as a negligible damage to normal tissues. After the treatment, the ultrasmall gold nanoclusters can be efficiently cleared by the kidney, thereby avoiding potential long term side effects caused by the accumulation of gold atoms in the body. Our data suggest that the ultrasmall peptide protected Au nanoclusters are a promising radiosensitizer for cancer radiotherapy.Comment: 15 Pages, 6 Figures, Scientific Reports 5, 201

Opposite Effects of HIV-1 p17 Variants on PTEN Activation and Cell Growth in B Cells

The HIV-1 matrix protein p17 is a structural protein that can act in the extracellular environment to deregulate several functions of immune cells, through the interaction of its NH2-terminal region with a cellular surface receptor (p17R). The intracellular events triggered by p17/p17R interaction have been not completely characterized yet. In this study we analyze the signal transduction pathways induced by p17/p17R interaction and show that in Raji cells, a human B cell line stably expressing p17R on its surface, p17 induces a transient activation of the transcriptional factor AP-1. Moreover, it was found to upregulate pERK1/2 and downregulate pAkt, which are the major intracellular signalling components involved in AP-1 activation. These effects are mediated by the COOH-terminal region of p17, which displays the capability of keeping PTEN, a phosphatase that regulates the PI3K/Akt pathway, in an active state through the serin/threonin (Ser/Thr) kinase ROCK. Indeed, the COOH-terminal truncated form of p17 (p17Δ36) induced activation of the PI3K/Akt pathway by maintaining PTEN in an inactive phosphorylated form. Interestingly, we show that among different p17s, a variant derived from a Ugandan HIV-1 strain, named S75X, triggers an activation of PI3K/Akt signalling pathway, and leads to an increased B cell proliferation and malignant transformation. In summary, this study shows the role of the COOH-terminal region in modulating the p17 signalling pathways so highlighting the complexity of p17 binding to and signalling through its receptor(s). Moreover, it provides the first evidence on the presence of a p17 natural variant mimicking the p17Δ36-induced signalling in B cells and displaying the capacity of promoting B cell growth and tumorigenesis

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Enhanced Radiation Therapy of Gold Nanoparticles in Liver Cancer

Gold nanoparticles (GNPs) were widely used in X-ray imaging and radiation therapy due to strong photoelectric effects and secondary electrons under high energy irradiation. As liver cancer is one of the most common forms of cancer, the use of GNPs could enhance liver cancer radiotherapy. We synthesized polyethylene glycol (PEG)-coated GNPs of two different sizes by chemical reduction reaction. Blood stability, cellular uptake, cytotoxicity and radiation therapy were investigated. A 3–5 nm red shift of SPR caused by interactions between PEG-coated GNPs and plasma indicated their good stability. Cellular uptake assay showed that PEG-coated GNPs would enhance an appreciable uptake. GNPs preferred to combine with blood proteins, and thus induced the formation of 30–50 nm Au-protein corona. GNPs were endocytosed by cytoplasmic vesicles, localized in intracellular region, and presented concentration dependent cell viability. Clonogenic assay illustrated that the PEG-coated GNPs could sensitize two liver cancer cell lines to irradiation